ABAD ACTIVITY IN ALZHEIMER'S DISEASE

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Changes in glucose metabolism have been observed in the brains of Alzheimer's disease sufferers. This suggests that neurons require an alternative energy source that can bypass glycolysis in order to produce energy. The oxidation of fatty acids is crucial at this point as the products of this catabolism can feed into the second stage of the respiratory cycle. ABAD is a key enzyme in the production of ketone bodies and sex steroid homeostasis in the brain and has been found to be up-regulated in AD (He et al., 1999, He et al., 2001, Lustbader et al., 2004). Additionally, ABAD is up-regulated under conditions of energy deprivation and increased ketogenesis (Du Yan et al., 2000, Yao et al., 2011). The abundance of Aβ present in the mitochondria in AD binds to ABAD and acts to either inhibit or alter the catalytic function of ABAD (Lustbader et al., 2004, Muirhead et al., 2010a). The effect of Aβ binding to ABAD could result in an energy deficit in the brain. -ABAD Activity Assay - using the fluorogenic probe cyclohexenyl amino naphthalene alcohol ((-)-CHANA), which when oxidized by ABAD produces cyclohexenyl amino naphthalene ketone (CHANK), which emits fluorescence at 520nm (Froemming and Sames, 2007, Muirhead et al., 2010b)-Mitochondrial integrity assays -Mass Spectrometry -Lipidomic and Fatty Acid Analysis Investigations into ABAD activity using (-)-CHANA activity assay suggest ABAD activity increases when glucose levels were decreased in mouse primary cortical neurons. This increase in activity is potentially controlled by posttranslational modifications of ABAD. Further effects downstream in lipid metabolism have also been observed upon changes in glucose levels. The increase of ABAD activity suggests that the cells are relying on the production of ketone bodies as an alternative energy source. Downstream effects of altering ABAD activity include changes in lipid content suggesting that the β -oxidation of fatty acids is altered. In AD, lipid changes have previously been noted along with a decline in cerebral metabolic glucose rate. The up-regulation of ABAD could be a protective mechanism and by increasing its activity the toxic effects of A β could be reversed.